Photoredox-Enabled Applications of Primary Amines as Alkylating Reagents

伯胺作为烷基化试剂的光氧化还原应用

• 批准号: 9760408
• 负责人: Jacob Geri
• 金额: $ 6.12万
• 依托单位: PRINCETON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-08-01 至 2022-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9760408
• 关键词: Affinity; Agrochemicals; Alcohols; Alkenes; Alkynes; Amines; Amino Acids; Ammonia; Ammonium; Architecture; Azides; Binding; Biological; Carbon; Carbon Dioxide; Carboxylic Acids; Catalysis; Cations; Chemicals; Chemistry; Complement; Complex; Copper; Coupling; Crown Ethers; Development; Diazomethane; Electron Transport; Electrons; Esters; Ethers; Gases; Goals; Hydrogen; Hydrogen Bonding; Lead; Methodology; Molecular; Natural Products; Nature; Organic Chemistry; Organic Synthesis; Pathway interactions; Pharmaceutical Chemistry; Pharmaceutical Preparations; Pharmacologic Substance; Preparation; Process; Reaction; Reagent; Research; Structure; System; Time; Transition Elements; Variant; Vertebral column; Work; base; c new; catalyst; chemical reaction; cost; drug discovery; drug efficacy; functional group; improved; side effect; skeletal; small molecule; tertiary amine

PROJECT SUMMARY/ABSTRACT Synthetic organic chemistry is essential for the preparation of complex small molecules used as drugs and agrochemicals, and advances in this field are driven by the discovery of new types of bond-forming chemical reactions. Research in reaction development allows wider pools of starting materials to be used for the construction of complex molecular architectures, and new fragment-coupling reactions which use widely available, bench stable, and biologically prevalent organic functional groups as reactive handles are highly impactful. Catalytic reactions that use such “native” functional groups, such as alcohols, carboxylic acids, and amines, can be immediately and widely deployed in medicinal chemistry settings for both small-scale drug discovery and in large-scale process development settings because of their greater opportunities for molecular diversification and the lower cost of the associated starting materials. In the proposed research, a new reactivity manifold for amines will be developed that will enable their use as electrophilic alkylating reagents in C-C bond forming reactions with ammonia as the sole byproduct. This contrasts with their traditional reactivity profile, which is limited to their use as nucleophiles in C-N bond forming reactions. A dual-catalysis approach is proposed which will use a strongly reducing photoredox catalyst to transfer a single electron to an alkylammonium cation to form an unstable, neutral ammonium radical. Typically, such hypervalent radicals decompose through loss of hydrogen atoms through N-H bond homolysis to generate hydrogen gas after self- annihilation. However, it is proposed that multiple hydrogen bonding interactions between an alkylammonium cation and a crown ether-type organocatalyst can be exploited to stabilize ammonia as a leaving group and bias the reaction pathway towards C-N bond homolysis, releasing a synthetically useful alkyl radical and ammonia. The alkyl radical thus generated will then be captured by organic and inorganic radicalphiles in C-C bond forming reactions proceeding through conjugate addition, radical aromatic substitution, and transition- metal cocatalyzed cross-coupling pathways. The intermediacy of a free alkyl radical makes this methodology highly modular, and it is anticipated that a wide variety of photoredox C-C coupling methodologies can be developed which will merge reductive C-N activation with oxidative C-CO2-, C-OH, and C-H activation.

项目摘要/摘要 合成有机化学对于制备用作药物的复杂小分子和 农业化学物质和该领域的进步是由于发现新型的粘结化学品类型的驱动 反应。反应发展的研究允许将起始材料池用于更广泛的库 建造复杂的分子体系结构和新的片段耦合反应，这些反应广泛使用 可用，稳定和生物学普遍的有机官能团作为反应性手柄高度高度 有影响力。使用此类“天然”官能团的催化反应，例如酒精，羧酸和 胺可以立即并广泛地部署在两种小型药物的医学化学环境中 发现和大规模过程开发设置，因为它们有更多的分子机会 多元化和相关起始材料的较低成本。在拟议的研究中，新的 将开发出胺的反应性歧管，以使其能够用作亲电饮酒试剂 C-C键与氨的反应作为唯一副产品。这与他们的传统反应性形成鲜明对比 剖面，仅限于在C-N键形成反应中用作核pholipses。双重分析方法是 提出的将使用强烈降低的Photoredox催化剂将单个电子转移到一个 烷基铵阳离子形成不稳定的中性铵自由基 通过N-H键同伊分解通过氢原子的丧失分解，自我后产生氢气 歼灭。但是，有人提出烷基铵之间的多种氢键相互作用 可以探索阳离子和冠状型有机催化剂，以稳定氨水作为离开组的氨和 偏向于C-N键同伊分析的反应途径，释放合成有用的烷基自由基和 氨。这样产生的烷基自由基将被C-C中的有机和无机自由基捕获 键形成通过共轭添加，自由基芳族取代和过渡的反应 金属共催化的交叉偶联途径。游离烷基激进的中间体使这种方法论 高度模块化，可以预见，可以是多种光电氧化物C-C耦合方法 开发的，将与氧化物C-CO2-，C-OH和C-H激活合并C-N活化。